Transforming growth factor-alpha (TGF-alpha) is a pleuroipotential cytokine with diverse biological effects, including the ability to influence the proliferation of normal and neoplastic epithelial cells and to induce angiogenesis. These biological activities can be elicited either via secretions of the mature form of TGF-alpha which is cleaved from the membrane bound precursor-proTGF-alpha, or by cell-cell interaction,where proTGF-alpha establishes contact with epidermal growh factor receptors on adjacent cells. There is much descrepancy in the current literature on the role of TGF-alpha in the malignant transformation process. The candidate of this application recerntly made the novel finding that eosinophils can express TGF-alpha. This offers new potential speculations for the role of the eosinophil and of TGF- alpha in tumor development and other pathological entities manifesting tissue eosinophilia. The major training goal of this Physician Scientist Award application is to provide the applicant, an Oral Pathologist, with didactic and practical training relevant to the study of eosinophil-derived TGF-alpha, to enable him to expand his experience and skills in molecular biology cancer research and pursue a career in biomedical research. The major research goals of this application are to investigate the expression of TGF-alpha by eosinophils in different tumors and oral lesions, the biological activities, the mechanism of delivery and the mechanism of activation of this cytokine in eosinophils. Phase I of this Award will include intensive coursework and training in the areas of cellular and tumor biology, molecular biology, mediators and biochemistry of the immune system in addition to a reseatch component which will include the examination of other neoplasms and other neoplasms and oral lesions associated with tissue eosinophilia. These lesions will be studied for the production and contribution of TGF-alpha by eosinophils using in situ hybridization, immunogistochemistry, morphometric analysis, and RNA blotting techniques. In phase II, this knowledge will be applied to study the biological activities of eosinophil derived TGF-alpha using in vitro and in vivo angiogenesis and mitogenesis assays. The mechanism by which eosinophils deliver TGF-alpha will be investigated using flow cytometry techniques and subcellular fractionation, The mode of activation and stimulation of eosinophils to produce TGF-alpha will be studied by exposing eosinophils from normal donors to a variety of eosinophil activating factors. These investigations will help to elucidate the role of eosinophils in tumor development and in other pathological entities. The study of the mechanisms by which eosinophils deliver TGF-alpha may contribute to the understanding of their function and mode of interaction with other cells. Identification of mediators which induce production of TGF-alpha by eosinophils can lead to the development of therapeutic methods for increasing of decreasing this effector/regulator function of eosinophils.